Journal of Occupational Medicine and Toxicology - Latest Comments

Value of biomonitoring for organic diisocyanate exposure

Heikki Savolainen — 2011-12-20T12:01:13Z

Dear Editor,

The careful study points out the requirements for correct interpretation of biomonitoring of exposure to diisocyanates (1). The initial urinary elimination half-lives of hexamethylene diisocyanate (2) or toluene diisocyanate monomers (3) are short which may limit the optimal sampling period immediately after the exposure peak (4). However, even end to the shift sampling can reveal the order of the magnitude of the exposure (5,6).

Finally, the mass spectrometric detection of the metabolites may have forensic value as they reveal the polyurethane source in e.g. the fire smoke victims (7).

1 Budnik LT, Nowak D, Merget R, et al. Elimination kinetics of diisocyanates after sepcific inhalative chanllenges in humans: mass spectrometry analaysis as a basis for biomonitoring strategies. J Occup Med Toxicol 2011; 6: 9

2 Rosenberg C, Savolainen H. Determination in urine of diisocyanate-derived amines from occupational exposure by gas chromatography-mass fragmentography. Analyst 1986; 111: 1069

3 Rosenberg C, Savolainen H. Determination of occupational exposure to toluene diisocyanate by biological monitoring. J Chromatogr 1986; 367: 385

4 Huynh CK, Vu-Duc T, Savolainen H. Occupational asthma due to isocyanate exposure: New orientations in the hygienic studies. Soz Präventivmed 1992; suppl. 2: S128

5 Maitre A, Berode M, Perdrix A, et al. Biological monitoring of occupational exposure to toluene diisocyanate. Int Arch Occup Environ Hlth 1993; 65: 97

6 Maitre A, Berode M, Perdrix A. Urinary hexane diamine as an indicator of occupational exposure to hexamethylene diisocyanate. Int Arch Occup Environ Hlth 1996; 69: 65

7 Rosenberg C, Savolainen H. Mass fragmentographic determination of urinary amine metabolites in rats exposed to degradation products from heated rgid polyurethane. J Chromatogr 1986; 358: 385

Cancer incidence ecological study in Rhineland-Palatinate, Germany, provides strong support for the ultraviolet B–vitamin D–cancer hypothesis

William B. Grant — 2010-07-19T11:50:01Z

The paper by Seidler et al. [1] provides strong support for the ultraviolet B–vitamin D–cancer hypothesis [2-5]. This study was designed to look for a potential association between pesticide exposure and cancer risk. By dividing the state into three categories, (small: >0 to 5 percent; medium: >5 to 20 percent; large: >20 percent area under wine cultivation), the study essentially divided the state into urban, mixed, and rural regions. It is reasonable to expect that those living in the rural region would have greater solar ultraviolet (UV) irradiance, and, based on the standardized incidence ratios (SIR) for non melanoma skin cancer (NMSC) and malignant melanoma for men shown in Table 4, that seems to be the case. The situation is not as clear for women as shown in Table 5, but those living in the urban regions had lower skin cancer and malignant melanoma SIR than those living in the mixed or rural regions.

As has been discussed in several papers, NMSC incidence and mortality rates serve as an index of solar UVB irradiance experienced by individuals and the population [6-11]. While the effect is stronger at latitudes equatorward of about 40º [9,10], there is evidence that the effect is also observed at higher latitudes in Europe [8,11]. Risk factors for melanoma include both UVA and UVB; with sunscreen use at high latitudes, UVA is the more important risk factor while for lower latitudes, sunburning from UVB is more important [12].

The role of solar UVB in reducing the risk of cancer can be estimated from the results in Tables 4 and 5. For this, I will assume that the lower 95% confidence interval (CI) for NMSC and malignant melanoma should be higher than the upper 95% CI interval for other cancers for the mixed or rural regions. For males, the cancers that satisfy this criterion for both regions are: stomach; colon, sigmoid & rectum; trachea, bronchus and lung; urinary tract; leukaemia; and all malignancies excluding C44. For females, the cancers that satisfy this criterion for both regions are: stomach; colon, sigmoid & rectum; trachea, bronchus and lung; cervix uteri; and ovary and other unspecified female genital organs. All of these cancers have been identified as having reduced risk from solar UVB in one or more ecological studies [5, 7, 13, 14].

However, puzzling is why some well-studied vitamin D-sensitive cancers did not show inverse correlations. For males, the reduced SIR was not statistically significant. Bladder cancer is vitamin D sensitive [5], but also sensitive to pesticides. Risk for prostate cancer is hypothesized to be linked to genetics and diet rather than vitamin D [15]. For non-Hodgkin’s lymphoma for both males and females, the SIR was significantly reduced in one region but not the other. Other studies have found NMSC correlated with risk of lymphoma [16]; however, at least in sunny countries, there is a benefit for UVB irradiance [17]. For females, the SIR for breast cancer was not significantly reduced. Alcohol is a risk factor for breast cancer [18], and in an affluent, wine-growing county in California, alcohol consumption is a risk factor for breast cancer [19]. The SIR for corpus uteri cancer was higher than for NMSC, malignant melanoma. Alcohol is also a risk factor for this cancer [20]. Thus, increased alcohol consumption in the winegrowing regions might explain these findings.

To extend this study, serum 25(OH) levels could be measured in summer for a cross-section of the older population living in each region.

In terms of policy, it would be worthwhile to recommend raising serum 25-hydroxyvitamin D levels to above 100 nmol/L at the population level, a value estimated to reduce all-cause mortality rates by 15-20% and health system costs by 10-15% [21-25]. In the absence of solar UVB, it would take 2000-5000 IU/day of vitamin D3 (cholecalciferol) to achieve this goal since each 1000 IU/day increases serum 25-hydroxyvitamin D levels by 15-25 nmol/L [26].

References
1. Seidler A, Hammer GP, Husmann G, König J, Krtschil A, Schmidtmann I, Blettner M. Cancer risk among residents of Rhineland-Palatinate winegrowing communities: a cancer-registry based ecological study. J Occup Med Toxicol. 2008 Jun 6;3:12.

2. Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol. 1980;9:227-31.

3. Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H, Mohr SB, Holick MF. The role of vitamin D in cancer prevention. Am J Public Health. 2006;96:252-61.

4. Garland CF, Gorham ED, Mohr SB, Garland FC. Vitamin D for cancer prevention: Global perspective. Ann Epi. 2009;19:468-83.

5. Grant WB, Mohr SB. Ecological studies of ultraviolet B, vitamin D and cancer since 2000. Ann Epidemiol. 2009;19:446-54.

6. Grant WB. A meta-analysis of second cancers after a diagnosis of nonmelanoma skin cancer: additional evidence that solar ultraviolet-B irradiance reduces the risk of internal cancers. J Steroid Biochem Mol 2007;103:668-74.

7. Grant WB. An ecologic study of cancer mortality rates in Spain with respect to indices of solar UV irradiance and smoking. Int J Cancer. 2007;120:1123-7.

8. de Vries E, Soerjomataram I, Houterman S, Louwman MW, Coebergh JW. Decreased risk of prostate cancer after skin cancer diagnosis: A protective role of ultraviolet radiation? Am J Epidemiol. 2007 165: 966-972.

9. Tuohimaa P, Pukkala E, Scelo G, Olsen JH, Brewster DH, Hemminki K, Tracey E, Weiderpass E, Kliewer EV, Pompe-Kirn V, McBride ML, Martos C, Chia KS, Tonita JM, Jonasson JG, Boffetta P, Brennan P. Does solar exposure, as indicated by the non-melanoma skin cancers, protect from solid cancers: Vitamin D as a possible explanation. Eur J Cancer. 2007;43:1701-12.

10. Grant WB. The effect of solar UVB doses and vitamin D production, skin cancer action spectra, and smoking in explaining links between skin cancers and solid tumours. Eur J Cancer. 2008;44:12-15.

11. Soerjomataram I, Louwman WJ, Lemmens VE, Coebergh JW, de Vries E. Are patients with skin cancer at lower risk of developing colorectal or breast cancer? Am J Epidemiol. 2008;167: 1421-9.

12. Gorham ED, Mohr SB, Garland CF, Chaplin G, Garland FC. Do sunscreens increase risk of melanoma in populations residing at higher latitudes? Ann Epidemiol. 2007;17:956-63.

13. Boscoe FP, Schymura MJ. Solar ultraviolet-B exposure and cancer incidence and mortality in the United States, 1993-2000. BMC Cancer. 2006;6:264.

14. Grant WB. Does Solar Ultraviolet Irradiation affect Cancer Mortality Rates in China? Asian Pac J Cancer Prev. 2007;8:236-42.

15. Grant WB. A multicountry ecological study of risk-modifying factors for prostate cancer: Apolipoprotein E 4 as a risk factor and cereals as a risk reduction factor. Anticancer Res. 2010;30;189-99.

16. Adami J, Frisch M, Yuen J, Glimelius B, Melbye M. Evidence of an association between non-Hodgkin's lymphoma and skin cancer. BMJ. 1995;310:1491-5.

17. Kricker A, Armstrong BK, Hughes AM, Goumas C, Smedby KE, Zheng T, Spinelli JJ, De Sanjose S, Hartge P, Melbye M, Willett EV, Becker N, Chiu BC, Cerhan JR, Maynadie M, Staines A, Cocco P, Boffeta P; for the Interlymph Consortium. Personal sun exposure and risk of non Hodgkin lymphoma: A pooled analysis from the Interlymph Consortium. Int J Cancer. 2008;122:144-54.

18. Grant WB. An ecologic study of dietary and solar ultraviolet-B links to breast carcinoma mortality rates. Cancer. 2002;94:272-81.

19. Keegan TH, Chang ET, John EM, Horn-Ross PL, Wrensch MR, Glaser SL, Clarke CA. Recent changes in breast cancer incidence and risk factor prevalence in San Francisco Bay area and California women: 1988 to 2004. Breast Cancer Res. 2007;9:R62.

20. Friberg E, Orsini N, Mantzoros CS, Wolk A. Alcohol intake and endometrial cancer risk: a meta-analysis of prospective studies. Br J Cancer. 2010;103:127-31.

21. Grant WB, Cross HS, Garland CF, Gorham ED, Moan J, Peterlik M, et al. Estimated benefit of increased vitamin D status in reducing the economic burden of disease in Western Europe. Prog Biophys Mol Biol. 2009;99:104–13.

22. Grant WB. In defense of the sun: An estimate of changes in mortality rates in the United States if mean serum 25-hydroxyvitamin D levels were raised to 45 ng/mL by solar ultraviolet-B irradiance. Dermato-Endocrinology, 2009;1:207–14.

23. Grant WB, Schwalfenberg GK, Genuis SJ, Whiting SJ. An estimate of the economic burden and premature deaths due to vitamin D deficiency in Canada, Molec Nutr Food Res. 2010 Mar 29. [Epub ahead of print]

24. Grant WB, Schuitemaker G. Health benefits of higher serum 25-hydroxyvitamin D levels in The Netherlands. J Steroid Biochem Molec Biol. 2010 Apr 14. [Epub ahead of print]

25. Zittermann A. The estimated benefits of vitamin D for Germany. Mol Nutr Food Res. 2010 Apr 1. [Epub ahead of print]

26. Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr. 2003;77:204-10.

Principal author's response to the August 24, 2009 comments by the chief editors

James Heller — 2010-03-11T14:11:34Z

December 21, 2009

Editors-in-Chief, Journal of Occupational Medicine and Toxicology

Prof. Axel Fischer (Email: axel.fischer@charite.de)
Head, Allergy Research Division
Charité - School of Medicine, Free University and Humboldt University of Berlin
Berlin, Germany

Prof. David A. Groneberg (Email: david.groneberg@charite.de)
Professor and Director, Institute of Occupational Medicine
Charité - School of Medicine, Free University and Humboldt University of Berlin
Berlin, Germany

Dear Sirs:

Re: Science and industry: Conflict-of-interests in the field of toxicology

I am writing to respond to your letter of August 24, 2009 commenting on our manuscript, New views on the hypothesis of respiratory cancer risk from soluble nickel exposure; and reconsideration of this risk's historical sources in nickel refineries, published in the JOMT in September 2009. I have been away this fall and this is my first opportunity to address certain issues raised by your letter; and to correct one matter in our paper.

First, the correction: our paper was originally submitted on February 15, 2008, not March 5, 2009. It was peer reviewed, subsequently rewritten, and resubmitted in revised form on March 5, 2009. Following further minor revisions, it was accepted for publication in early June 2009, and published in September 2009. Please make the necessary revisions to the online paper on your journal’s website.

Second, it is truly unfortunate that you have chosen to write this letter. You and your publisher had the option at the time of the manuscript’s first submission in February 2008 to consider it for publication or to refuse its consideration when it raised questions of ‘integrity’ and ‘conflict of interest’ in your minds. However, to choose this third option of passing the paper and ourselves through an intensive, 18 month peer review, rewriting and revision process, before revealing your position to your readership and ourselves was underhanded and mean spirited behaviour, and likely violates codes of ethical conduct for peer reviewed scientific journalism.

Let me provide you with some background concerning the sponsorship issue. Since the current regulatory view is that all nickel compounds are carcinogenic (viz. IARC’s March 2009 Meeting on nickel), all new hypotheses testing their carcinogenicity must, perforce, be ‘negative’ hypotheses and, in your opinion therefore, ‘pro-industry’ hypotheses. In fact, our hypothesis arose from observations by environmental professionals in several nickel refineries that soluble nickel was unwarrantedly being characterized as carcinogenic; and that the supporting evidence for this opinion appeared to be concentrated in KNR’s epidemiology. As the previous administrative head of a government agency legislatively mandated to investigate industrial disease in Ontario, I had a great deal of experience in this field and was asked to investigate the basis for the opinion concerning soluble nickel’s carcinogenicity. At no time was my research on this issue interfered with or my views prescribed. On the contrary, I had access to industry professionals and data from around the world whenever I needed information unavailable through public channels, thanks to my co-author, Dr. Bruce R. Conard. Consequently, the scientific judgments reached in the submitted manuscript and its integrity rest entirely on my shoulders since I enjoyed a de facto arm’s length relationship with my sponsors. You couldn’t have known that in advance but this fact goes to the heart of my concerns about your reactionary and self-righteous behaviour.

It is reflexively assumed that industry sponsored research is inherently biased whereas research originating in academic institutions or public health agencies is inherently unbiased; and that the peer reviewed scientific literature provides a fact based body of knowledge upon which sound regulatory policy on chemicals can be constructed. Our ability to look beyond the published literature, however, has shown that its conclusions cannot always be taken at face value; and that regulators who rely unquestioningly on this source of information to build policy are liable to serious errors in scientific judgment.

This brings me to the freedom of speech issue. Your readers should appreciate that the publisher disallowed publication of fifteen files of additional data and information attached to our paper out of fear of infringing the intellectual property rights of their original owners. Yet we had already confirmed that this information was in the public domain and had been filed previously with regulators (e.g. environmental data) or with nickel researchers who eventually published their work [e.g. Thornhill (1986) was filed with Sir Richard Doll’s ICNCM Committee whose research appeared in ICNCM (1990)], or with other publicly accessible repositories. Those files were intended to support the conclusions in our paper and reconsideration of regulatory policy on nickel. Even worse, the publisher suggested rewording of a sentence in the concluding remarks of the abstract to our paper, again fearing liability with the strong implication that it would not be published had we refused the proposed change. This is censorship! So it is ironic indeed that you are taking pride in your liberal views on freedom of speech when we were forced to comply with your publisher’s censorial dictates.

The JOMT informs us that there have been 1,488 accesses to the article since its publication (not including PubMed Central or other archive sites), a level the journal rates as ‘Highly Accessed’ relative to age. In the 3+ months since its publication, however, the paper has not generated a single comment. This can only mean that, by tainting honestly conducted research with innuendoes of bias, your reckless letter has effectively discouraged debate and discussion by the interested readership. This result is antithetical to the aims of science, scholarship and journalistic integrity. I write, therefore, to request a retraction of your remarks and an apology. I also request that these responses be posted alongside this letter and our article on the JOMT website.

Yours sincerely,

James G. Heller, PhD, DECH

c.c. Bruce R. Conard

Response to comments posted by Drs David A. Groneberg and Axel Fischer, JOMT Editors-in-Chief

Adriana Oller, Ph.D., DABT — 2010-03-11T14:10:47Z

In their comments, JOMT editors suggest that arguments made in the Heller et al. paper were not supported by solid scientific data, but they decided to publish this paper because "it can be regarded as a typical example of the approach of private companies towards the scientific discussion of compound toxicity and carcinogenicity," among other reasons. If the editors were of the view that the Heller et al. paper was not based on solid science, then it was their responsibility to reject it, as the whole purpose of the peer-review process is to ensure publication of sound science. Whether the author of a paper is an industry scientist or an academic scientist, different opinions can aid the scientific discourse as long as they are supported by solid, transparent data and subjected to the process of thorough peer review. No paper should be published unless this criterion is met.

As a toxicologist employed by the nickel industry (NiPERA), I believe that the nickel industry can and does support and publish scientifically rigorous studies. Although I disagree with the way that Heller et al. interpreted the nickel animal toxicology data and believe that the overall assertive tone of the paper goes beyond what the data warrants, this paper raises awareness about some key nickel refinery issues that could have (in a different format) contributed to the scientific debate on the carcinogenicity of soluble nickel. However, as it stands now, the JOMT missed an opportunity to assure that Heller’s paper meets accepted scientific standards. Publication of Heller’s paper in an appropriate format might have provided useful input to scientific debate in this area.

Adriana R. Oller, Ph.D, DABT
Toxicologist with NiPERA (Nickel Producers Environmental Research Association)

Science and industry: Conflict-of-interests in the field of toxicology

David A. Groneberg — 2009-08-24T10:45:55Z

In this report by Heller et al., two companies which are involved in the exploration, mining, and processing of nickel, sponsored a study that questions soluble nickel as a carcinogenic substance.
Although the editors agreed to publish this hypothesis, we feel that some clarifying words should be stated:

1) The editors-in-chief and the publisher questioned the integrity of the article on first sight. The first impression was to reject the article due to the magnitude of the conflict of interest. This conflict of interest arises from the nature of the sponsoring companies: The companies are Vale Inco and Falconbridge Ltd. Vale Inco is the second largest mining company in the world, with a market capitalization of more than US$ 125 billion and over 12,000 employees worldwide with net sales last year of over US$8 billion last year [1]. The second company Falconbridge Limited was a Canadian natural sources company that was absorbed in 2006.
2) After reviewing the article, the editors-in-chief decided to publish the article because: a) the conflict of interest is clearly stated: “Drs. Heller and Conard received financial support from Vale Inco Ltd. for the preparation of this paper. Dr. Heller also received financial support previously from Falconbridge Ltd. to conduct the underlying research in this paper. Mr. Thornhill has received no financial support.” b) the article reviews a large amount of studies and data – although partly onesided – that should be discussed by other non-biased scientists and c) it can be regarded as a typical example of the approach of private companies towards the scientific discussion of compound toxicity and carcinogenity.

The authors hypothesize that the true causes of historical lung cancer risk at certain nickel refineries may lie in other exposures, including insoluble nickel compounds, arsenic, sulphuric acid mists and smoking. This hypothesis is based by their failure to accurately identify the source(s) of observed lung cancer risk in one nickel refinery (KNR).
Freedom of speech is an important issue in science but also, the integrity of arguments represents a keystone when it comes to the discussion of toxic and carcinogenic effects. Ideally, scientists that are involved in research on nickel toxicity should now discuss the different points raised by Heller et al. in order to substantiate the knowledge on nickel toxicity.

David A. Groneberg, MD
Editor-in-Chief, Journal of Occupational Medicine and Toxicology
Professor of Medicine/Occupational Medicine

Axel Fischer, MD
Editor-in-Chief, Journal of Occupational Medicine and Toxicology
Professor of Medicine/Allergy

[1] http://www.inco.com/
[2] http://www.xstrata.com/

its a good report about music

Gul Ghuttai — 2009-01-27T18:28:18Z

HI<br><br> this is a very informative article..i learned a lot from it. I want to ask that is music also toxic to brain? are there new experiments done in this regard?

DENTAL ASSISTANTS (and the rest of the dental personnel) MUST BE GLAD

Servando Pérez-Domínguez — 2008-08-21T16:16:22Z

INDEED, dental assistants and the rest of the dental personnel, including dentists, must be glad because their professions (considered by the International Labour Organization as professions at risk for Chronic Mercury Poisoning), are, at last, really starting to be better studied, and, therefore, the dangers are timidly starting to be not fully hidden at the Faculties of Dentistry, Medicine, etc., or ‘underneath’ research projects, books or articles written by authors with various conflicts of interest, empty words, promises... We all know (the FDA had to recently recognised it publicly: www.mercuriados.org/es/pag254), that also those who have in their mouths dental amalgam fillings are at risk (but this was not the aim of this article).

Most probably, future generations will hardly understand why such dental material was still generally used in the 21st century, without at least considering the Precautionary Principle, and also knowing that, as Prof. Dr. Maths Berlin stated in the 2003 Report for the Swedish Dental Material Commission “Mercury in Dental-Filling Material--An Updated Risk Analysis in Environmental Medical Terms" — www.toxicteeth.org/Berlinbilaga.doc: “…fully adequate and less toxic alternatives are available” (p. 25).

All in all, our most sincere CONGRATULATIONS to the authors for conducting the research and for writing the article, and also our sincere CONGRATULATIONS to the Journal of Occupational Medicine and Toxicology for publishing the article, and, thus, allowing the readers to continue learning about the subtle (but relevant) health effects of such powerful heavy metal.

Santiago de Compostela, 20th August 2008

Servando.

www.mercuriados.org

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Prof. Servando Pérez-Domínguez

(President of the mercury poisoned patient organisation MERCURIADOS, and Medicine Student)

University of Santiago de Compostela, Spain

Email: servando.mercuriados@gmail.com

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"Real science is the one always open for constructive discussion" (José Ortega y Gasset).

Need for greater restraint in prescribing skeletal muscle relaxants specially to the elderly

Samuels hurstong — 2008-01-02T09:14:39Z

I would like to add to this article by pointing out the potential toxicity of skeletal muscle relaxant at theraputic doses, especially in the elderly population. I am interested in geriatric medicine, as guest faculty at UCSF we have seen a spate of confusion and agitation associated with the prescription of this class of drugs recently. Poly pharmacy in the elderly is something that needs to be looked at. This class of agents in particular can be associated with vast manifestations.

very topical and informative

Samuels hurstong — 2008-01-02T09:14:13Z

I was recently privy to the treatment of a patient with cyclobenzaprine overdose. This article details very well the protocols used in the management of such patients. There is very little data regards the management of such patients and this article certainly adds to the body of literature in this field. I must convey my regards to the author(s) for such a presentation.